Control of Drosophila wing growth by morphogen

描述（由申请人提供）：本资助的主要目标是确定动物发育过程中形态因子如何控制器官生长。形态因子是分泌的信号分子，通过发育中的组织传播，控制基因表达、模式、极性和生长。在所有多细胞动物中，从海绵到人类，形成因子的主要超家族都是保守的。了解它们的工作原理对人类健康有着巨大的影响，因为它们的活动和信号转导途径的遗传和环境扰动会导致各种发育和神经障碍以及各种癌症。因此，形态原的研究对于开发诊断和治疗人类疾病的工具至关重要，这是美国国立卫生研究院的中心任务。我们过去使用果蝇进行的研究有助于确定三个分泌蛋白超家族的成员，无翼/ int (Wnts)，骨形态发生蛋白（BMPs）和刺猬（Hhs）都是真正的形态发生蛋白。最初，这些研究集中于确定这些分子控制基因表达、模式和极性的逻辑和分子机制。在这里，我们转向更具挑战性的问题，即它们如何组织增长。在拟议的研究中，我们将测试和扩展我们基于我们最近发现的关于果蝇无翼（Wg） （Wnt超家族的创始成员）如何控制发育中的翅膀的急剧扩张的新模型，这是形态发生作用的经典范例。在这个模型中，Wg和第二种形态原Decapentaplegic (Dpp)，一种BMP，通过调节选择基因、退化基因（vg）和一种定义“翅膀”状态的转录因子的表达，共同作用维持翅膀细胞的生长，并将新细胞招募到翅膀原基中。我们有初步证据表明，这一过程中的关键事件是由vg基因中的单个增强子元件介导的，该元件整合了Wg和Dpp输入，以及第三个“招募”信号，该信号依赖于保守的wart - hippo肿瘤抑制通路的瞬时激活。我们将结合遗传、转基因和分子方法来建立这三种信号系统的作用，以及通过这种增强子整合它们的分子机制。此外，我们将分析形态依赖的翅膀生长的三个限制，即形态依赖的扩散能力，来自周围组织的JAK/Stat信号的抑制作用，以及对全身类固醇激素Ecdysone水平变化的依赖。这些实验要么证实并推进我们控制器官生长的模型——这是所有动物中一个基本的、尚未解决的问题——要么导致新的、可测试的假设。

DESCRIPTION (provided by applicant): The main goal of this grant is to determine how morphogens control organ growth during animal development. Morphogens are secreted signaling molecules that spread through developing tissues and control gene expression, pattern, polarity and growth. The major superfamilies of morphogens are conserved in all multi- cellular animals, from sponges to man. Understanding how they work has enormous implications for human health, as genetic and environmental perturbations of their activities and signal transduction pathways cause diverse developmental and neurological disorders as well as a wide range of cancers. Research on morphogens is thus critical for developing diagnostic and therapeutic tools to treat human disease, a central mission of the NIH. Our past studies, using Drosophila, were instrumental in establishing that members of three superfamilies of secreted proteins, Wingless/Ints (Wnts), Bone Morphogenetic Proteins (BMPs) and Hedgehogs (Hhs) all function as bona fide morphogens. Initially these studies were focused on determining both the logic and molecular mechanisms by which these molecules control gene expression, pattern and polarity. Here, we turn to the more challenging problem of how they organize growth. In the proposed research, we will test and extend a new model we have posited for growth based on our recent discoveries about how Drosophila Wingless (Wg), a founding member of the Wnt superfamily, controls the dramatic expansion of the developing wing, a classic paradigm for morphogen action. In this model, Wg and a second morphogen Decapentaplegic (Dpp), a BMP, act together to sustain the growth of wing cells and to recruit new cells into the wing primordium by regulating expression of the selector gene, vestigial (vg), and a transcription factor that defines the "wing" state. We have preliminary evidence that the key events in this process are mediated by a single enhancer element in the vg gene, which integrates Wg and Dpp input, as well as a third "recruitment" signal that depends on transient activation of the conserved Warts-Hippo tumor suppressor pathway. We will combine genetic, transgenic and molecular approaches to establish the roles of all three signaling systems, as well as the molecular mechanism(s) by which they are integrated by this enhancer. In addition, we will analyze three limits to morphogen-dependent wing growth, namely the capacity of morphogens to spread, the inhibitory action of JAK/Stat signaling from surrounding tissue, and the reliance on changing levels of the systemic steroid hormone Ecdysone. These experiments will either confirm and advance our model for the control of organ growth- a fundamental, unsolved problem in all animals - or lead to new, testable hypotheses.